In summary, we have accomplished the total synthesis of
nocardioazine B from tryptophan in 11.8% overall yield with
the longest linear sequence of 10 steps. This synthesis established
the absolute stereochemistry of the natural product. The extension
of this chemistry towards the total synthesis of nocardioazine
A and novel nocardioazine analogues for biological evaluation is
under way and will be reported in due course.
We acknowledge financial support from the Hong Kong
Research Grants Council (Projects: PolyU 5638/07M; PolyU
5040/10P; PolyU 5037/11P); Fong Shu Fook Tong Founda-
tion and Joyce M. Kuok Foundation; The Hong Kong Poly-
technic University (PolyU 5636/08M; PolyU 5634/09M); The
Shenzhen Bureau of Science, Technology and Information
(JC200903160367A, ZD200806180051A, JC201005260-102A
& JC201005260220A), NSFC (21072007) and GDSFC
(10151805704000005).
Scheme 6 (a) HATU, HOAT, DMF, TEA; (b) HCHO(aq.), HOAc,
Notes and references
NaBH3CN, CH3OH.
1 R. Raju, A. M. Piggott, X. C. Huang and R. J. Capon, Org. Lett.,
2011, 13, 2770–2773.
reagents/conditions did not succeed. The failure to undergo
the expected coupling reaction is presumably attributed to
steric effects exerted by the N-methyl group in 20.
2 (a) L. Wang, Z. S. Xu and T. Ye, Org. Lett., 2011, 13, 2506–2509;
(b) H. Liu, Y. Q. Liu, Z. S. Xu and T. Ye, Chem. Commun., 2010, 46,
7486–7488; (c) X. G. Gao, Y. Q. Liu, S. Q. Kwong, Z. X. Xu and T. Ye,
Org. Lett., 2010, 12, 3018–3021; (d) S. Li, Z. Chen, Z. S. Xu and T. Ye,
Chem. Commun., 2010, 46, 4773–4775; (e) Z. Chen, L. Song, Z. S. Xu
and T. Ye, Org. Lett., 2010, 12, 2036–2039; (f) Y. Jin, Y. Q. Liu,
Z. Wang, S. Q. Kwong, Z. S. Xu and T. Ye, Org. Lett., 2010, 12,
1100–1103; (g) S. Liang, Z. S. Xu and T. Ye, Chem. Commun., 2010, 46,
153–155; (h) B. Chen, L. Dai, H. Zhang, W. Tan, Z. S. Xu and T. Ye,
Chem. Commun., 2010, 46, 574–576; (i) S. Li, S. Liang, W. Tan, Z. S. Xu
and T. Ye, Tetrahedron, 2009, 65, 2695–2702; (j) S. Li, S. Liang, Z. S. Xu
and T. Ye, Synlett, 2008, 569–574; (k) Q. Ren, L. Dai, H. Zhang,
W. Tan, Z. S. Xu and T. Ye, Synlett, 2008, 2379–2383; (l) Z. Y. Chen
and T. Ye, New J. Chem., 2006, 30, 518–520; (m) H. W. Pang, Z. S. Xu,
Z. Y. Chen and T. Ye, Lett. Org. Chem., 2005, 2, 699–702; (n) H. W.
Pang, Z. S. Xu and T. Ye, Lett. Org. Chem., 2005, 2, 703–706; (o) H.
Chen, Z. S. Xu and T. Ye, Tetrahedron, 2005, 61, 11132–11140;
(p) Z. Y. Chen, J. G. Deng and T. Ye, ARKIVOC, 2003, 268–285;
(q) Y. G. Peng, H. W. Pang and T. Ye, Org. Lett., 2004, 6, 3781–3784;
(r) Z. S. Xu, Y. G. Peng and T. Ye, Org. Lett., 2003, 5, 2821–2824.
3 (a) K. Ishida, H. Matsuda, M. Murakami and K. Yamaguch, Tetra-
hedron, 1996, 52, 9025–9030; (b) F. S. Guzman and J. B. Glober,
J. Nat. Prod., 1992, 55, 931–939; (c) P. R. Sanchis, S. A. Savina,
The rate of fragment condensation should be facilitated by
using a less sterically demanding nucleophile. Accordingly, we
decided to couple the acid portion (3) directly to ester 17 and
postpone the N-methylation to a later stage in the synthesis. Thus,
addition of HATU, HOAT and triethylamine to a solution of acid
3 and amine 17 in DMF provided 21 in 60% yield (Scheme 6).
Reductive N-methylation of 21 by an identical procedure as
described for 19 gave rise to precursor 2 in 69% yield, which set
to the stage for the final diketopiperazine formation. Literature
precedent suggested that diketopiperazine formation could be a
spontaneous process.13 Several attempts at the direct formation of
diketopiperazine from 2 were explored. Thus, treatment of 2 with
trifluoroacetic acid in dichloromethane followed by neutralization
with excess triethylamine failed to generate the corresponding
diketopiperazine. On the other hand, TMSI-mediated4 cleavage
of the two Boc carbamates of 2 accompanied by cyclisation of the
carbomethoxy function onto the proximal NH group produced a
mixture of nocardioazine B (1) and the double bond isomerized
analogue 22 as an inseparable 1 : 1 mixture in 52% combined
yield. Gratifyingly, upon treatment of 2 with TMSOTf in the
presence of DIPEA, nocardioazine B (1) can be obtained as a
single isomer in 78% yield (Scheme 6).
´
F. Albericio and M. Alvarez, Chem.–Eur. J., 2011, 17, 1388–1408.
4 M. K. Depew, S. P. Marsden, D. Zatorska, A. Zatorski,
W. G. Bornmann and S. J. Danishefsky, J. Am. Chem. Soc.,
1999, 121, 11953–11963.
´ ´ ´
5 C. S. Lopez, C. Perez-Balado, P. Rodrıguez-Grana and A. R. Lera,
Org. Lett., 2008, 10, 77–80.
6 D. Crich and A. Banerjee, Acc. Chem. Res., 2007, 40, 151–161.
7 V. R. Espejo, X. B. Li and J. D. Rainier, J. Am. Chem. Soc., 2010,
132, 8282–8284.
1
The synthetic material displayed H and 13C NMR spectra
identical to those reported by Capon and co-workers.1 The
optical rotation of synthetic 1, [a]2D5 = ꢀ20 (c 0.1, CH3OH), was
of comparable in magnitude but opposite in sign to that
reported for the natural product, [a]2D5 = +17 (c 0.04, CH3OH),
establishing the absolute configuration of the nocardioazine B
(Fig. 2) as enantiomeric to what is shown in Fig. 1.
8 (a) M. Bruncko, D. Crich and R. Samy, J. Org. Chem., 1994, 59,
5543–5549; (b) J. A. Gonzalez-Vera, M. T. Garcıa-Lopez and
´ ´ ´
R. Herranz, J. Org. Chem., 2007, 72, 5395–5398.
9 W. Yu, Y. Mei, Y. Kang, Z. Hua and Z. Jin, Org. Lett., 2004, 6,
3217–3219.
10 R. S. Lott, V. S. Chauhan and C. H. Stammer, J. Chem. Soc.,
Chem. Commun., 1979, 495–496.
11 P. Ventosa-Andre
M. T. Garcıa-Lopez and R. Herranz, Bioorg. Med. Chem., 2008,
16, 9313–9322.
s, J. A. Gonzalez-Vera, A. M. Valdivielso,
´ ´
´
´
12 (a) S. Takano, M. Moriya, Y. Iwabuchi and K. Ogasawara, Chem.
Lett., 1990, 109–112; (b) C. Mukai, T. Yoshida, M. Sorimachi and
A. Odani, Org. Lett., 2006, 8, 83–86.
13 (a) K. A. Carpenter, G. Weltrowska, B. C. Wilkes, R. Schmidt and
P. W. Schiller, J. Am. Chem. Soc., 1994, 116, 8450–8458;
(b) R. Krishnamoorthy, L. D. Vazquez-Serrano, J. A. Turk,
J. A. Kowalski, A. G. Benson, N. T. Breaux and M. A. Lipton,
J. Am. Chem. Soc., 2006, 128, 15392–15393.
Fig. 2 Absolute configuration of nocardioazine B.
4346 Chem. Commun., 2012, 48, 4344–4346
c
This journal is The Royal Society of Chemistry 2012